Relating sex-bias in human cortical and hippocampal microstructure to sex hormones

Determining sex-bias in brain structure is of great societal interest to improve diagnostics and treatment of brain-related disorders. So far, studies on sex-bias in brain structure predominantly focus on macro-scale measures, and often ignore factors determining this bias. Here we study sex-bias in cortical and hippocampal microstructure in relation to sex hormones. Investigating quantitative intracortical profiling in-vivo using the T1w/T2w ratio in 1093 healthy females and males of the cross-sectional Human Connectome Project young adult sample, we find that regional cortical and hippocampal microstructure differs between males and females and that the effect size of this sex-bias varies depending on self-reported hormonal status in females. Microstructural sex-bias and expression of sex hormone genes, based on an independent post-mortem sample, are spatially coupled. Lastly, sex-bias is most pronounced in paralimbic areas, with low laminar complexity, which are predicted to be most plastic based on their cytoarchitectural properties. Albeit correlative, our study underscores the importance of incorporating sex hormone variables into the investigation of brain structure and plasticity.

positive correlation between skewness and mean T1w/T2w, blue represent negative correlations.Source data are provided as a Source Data file.Supplement 7. Non-significant microstructural differences between NC females (Cohen's d).NC females (n = 284) were divided by hormone estimations according to self-reported days after menstruation.Columns are the three microstructural measures T1w/T2w mean, T1w/T2w skewness, and the microstructural gradient.Purple areas are parcels which had higher values for females in the high estrogen (n = 184) or high progesterone (n = 113) group, orange showshad higher values for NC females in the respective lower hormonal group (all Cohen's d; nlow estrogen = 100; nlow progesterone = 171).Note that no parcel was significant at an FDR-threshold.Source data are provided as a Source Data file.
Supplement 8. Split-correlation of 1000 random permutations for all hormonal contrasts and each microstructural measure.For every split, we computed the contrast between males and females, randomly choosing only a subsample of males, such that n(males) = n(females).We did so matching n(males) to n(OC females) = 170 in A), n(males) to n(High estrogen females) = 184 in B), n(males) to n(Low estrogen females) = 100 in C), n(males) to n(High progesterone females) = 113 in D) and n(males) to n(Low progesterone females) = 171 in E).We then computed the internal consistency for this randomly chosen male subsample by correlating the effect sizes of this contrast with the Cohen's d effect sizes of an equally sized and randomly chosen subsample of males.Datapoints represent correlation values (Pearson's r) for each split.The median is shown as the central mark in each subpanel, the box indicates 25 th and 75 th percentile; whiskers include all values not considered outliers (1.5*IQR from the quartile).Source data are provided as a Source Data file.Supplement 9. Effect sizes for sex differences in T1w/T2w profile mean (B), skewness (C) and microstructural gradient (D) for each of n=400 Schaefer parcel, and how these effects change depending on which female subgroups males are compared to, each parcel colored by cortical type (A).The diagonal shows the sex-different effect size distributions per comparison, and how they shift depending on the contrast.Scatter plots show correlation between two respective effects, and the deviance of each parcel from the other contrast's effect size.The first column (black box) is the original all females (n = 594) vs. all males (n = 499) sex difference effect, compared to all contrasts between males and female subgroups.All values represent Cohen's d values (females -males).Parcels are colored by cortical types (left).Source data are provided as a Source Data file.

Only female donor.
Only male donors.Supplement 10.Spatial overlap between effect maps of sex differences for the microstructural gradient, profile mean and profile skewness, split by AHBA donor-sex.Top and bottom are the same analysis, but considering only the female (top, n=1) and male (bottom, n =5) AHBA donors to derive the transcriptomic maps.Transcriptomic maps of genes are sorted by categories: sex hormone synthesis related genes, androgen receptor related, estrogen receptor related genes, and progesterone receptor related genes.We test for spatial specificity by comparing against the principal component of all genes (baseline).Shades of red represent positive r-values, shades of blue represent negative correlations; circle size and shading indicate size of correlation.p-values < 0.05 after correcting for auto-correlations using spin-testing are marked with a black outline.Source data are provided as a Source Data file.mean, the peak value for T1w/T2w skewness is r = .21,and the highest correlation between ICV and a gradient parcel is -.21.Source data are provided as a Source Data file.

Genes
Gradient corr .Spatial overlap between effect maps of sex differences for the microstructural gradient, profile mean and profile skewness.The table shows correlations and their respective p values, and spin-corrected p-values (one-sided; determined by where the empirical r-value falls in the distribution of 1000 random spherical spin-permutations).

Gradie
Transcriptomic maps of genes are of the following categories: sex hormone synthesis related genes, androgen receptor related, estrogen receptor related genes, and progesterone receptor related genes.
T1w/T2w signal intensity profiling with additional covariates.Shown are z-values for the (females (n = 594) > males (n = 499)) contrast, controlling for family structure (including the interaction between twin status and family status) and cortical thickness, FDR controlled Cohen's d.Blue shades represent Cohen's d < 0, indicating higher values in males; red shades represent Cohen's d > 0, indicating higher values in females.Source data are provided as a Source Data file.Supplement 4. Associations between cortical thickness and microstructural sex differences.(A) FDRthresholded Cohen's d maps showing significant sex differences (females (n = 594) > males (n = 499)) in cortical thickness, Red colors represent microstructural values were higher for females, blue represent values higher for males.B) Associations between sex differences in cortical thickness and effect values (Cohen's d for each of the 400 Schaefer parcels) for each of the T1w/T2w profile-based intracortical measures.The upper row visualizes zero-distributions between random hierarchies and effect maps in comparison to the statistical r-value, the bottom row plots cortical thickness sex differences on the X-axis, and sex differences of microstructural measures on the Y-axis.Source data are provided as a Source Data file.Supplement 5. Internal Consistency Hippocampus.Boxplots represent Pearson's r-values between unthresholded t-statistics resulting from two respective split-halves of the sample (n = 1000 permutations) comparing the microstructural mean of the left and right hippocampus between females and males, indicating their reliability.The median is shown as the central mark, the box indicates 25 th and 75 th percentile; whiskers include all values not considered outliers (1.5*IQR from the quartile).Source data are provided as a Source Data file.